1175 premenopausal women whose date of last menstrual period was known were followed up for up to 20 years (average 8 years) after surgery for breast cancer. 525 patients were in the follicular phase and 650 in the luteal phase. We observed 192 unfavourable events among patients operated on during the follicular phase (36.6%) and 192 among patients operated on during the luteal phase (29.6%). The effect of phase was restricted to patients with positive axillary nodes. The 5-year relapse-free survival was 75.5% in 246 node-positive patients operated on during the luteal phase and 63.3% in 190 node-positive patients who had surgery during the follicular phase. The hazard ratio at Cox multivariate analysis was 1.329 for all patients (p = 0.006) and 1.431 for node-positive patients (p = 0.03). In our study, premenopausal patients with breast cancer and positive axillary nodes operated on during the luteal phase had a significantly better prognosis than patients operated on during the follicular phase. It may be that the processes of cell metastases, such as loss of adhesiveness, may be enhanced by high concentrations of unopposed oestrogens or by reduced activity of natural killer cells during the first half of the menstrual cycle.

Immunotherapy of chronic viral diseases with vaccines is an important but unproven concept. We investigated the effect of a vaccine containing recombinant glycoprotein D (gD2) of herpes simplex virus type 2 (HSV-2) on the frequency of symptomatic outbreaks in patients with genital herpes. 98 patients with documented genital herpes who reported 4-14 recurrences per year were enrolled in a double-blind, placebo-controlled trial. Subjects received injections of either 100 micrograms gD2 in alum or alum alone (placebo) at 0 and 2 months, and recurrences were documented for 1 year. The vaccine was well tolerated. gD2 recipients reported fewer recurrences per month than placebo recipients (mean 0.42 [SE 0.05] vs 0.55 [0.05]; p = 0.055), had fewer virologically confirmed recurrences per month (0.18 [0.03] vs 0.28 [0.03]; p = 0.019), and had a lower median number of recurrences for the study year (4 [range 0-17] vs 6 [0-15]; p = 0.039). Neither genital recurrence nor the placebo vaccine had any discernible effect on HSV-2-specific antibody responses, but gD2 vaccine boosted neutralising antibodies to HSV-2 fourfold and gD2-specific titres sevenfold over baseline levels. These results inspire optimism about the potential use of vaccine for the treatment of chronic, recurring viral diseases.

In a prospective, randomised single-blinded secondary prevention trial we compared the effect of a Mediterranean alpha-linolenic acid-rich diet to the usual post-infarct prudent diet. After a first myocardial infarction, patients were randomly assigned to the experimental (n = 302) or control group (n = 303). Patients were seen again 8 weeks after randomisation, and each year for 5 years. The experimental group consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and alpha-linolenic acids confirmed by measurements in plasma. Serum lipids, blood pressure, and body mass index remained similar in the 2 groups. In the experimental group, plasma levels of albumin, vitamin E, and vitamin C were increased, and granulocyte count decreased. After a mean follow up of 27 months, there were 16 cardiac deaths in the control and 3 in the experimental group; 17 non-fatal myocardial infarction in the control and 5 in the experimental groups: a risk ratio for these two main endpoints combined of 0.27 (95% CI 0.12-0.59, p = 0.001) after adjustment for prognostic variables. Overall mortality was 20 in the control, 8 in the experimental group, an adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p = 0.02). An alpha-linolenic acid-rich Mediterranean diet seems to be more efficient than presently used diets in the secondary prevention of coronary events and death.

Coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are more effective than medical treatment for the management of ischaemic heart disease. However, patients with single-vessel involvement have been excluded from prospective comparisons of the two methods. We have carried out such a comparison in patients with isolated proximal left anterior descending artery stenosis, conserved left ventricular function, and documented ischaemia. Eligible patients presenting to a single centre were randomly assigned PTCA (68 patients) or left internal mammary grafting (66). The procedures were technically feasible in all cases. The incidence of in-hospital complications was 2% (perioperative myocardial infarction) for CABG and 3% (emergency CABG for acute closure) for PTCA. Clinical and functional status improved similarly in both groups. However, patients in the PTCA group took more antianginal drugs. At median follow-up of 2.5 years, 86% of CABG-treated and 43% of PTCA-treated patients were free from adverse events (p < 0.01; relative risk 2.0 [95% CI 1.7-2.3]). The adverse events that explain this difference were restenosis (32%) requiring subsequent surgical (16%) or percutaneous (15%) revascularisation (1% had medical therapy). Rates of cardiac death and myocardial infarction did not differ between the groups. Both CABG and PTCA improve the clinical status of symptomatic patients with single-vessel coronary artery disease. If patient and physician accept the risk of restenosis and reintervention associated with PTCA, this procedure remains a suitable option and a simpler initial alternative to CABG.

As part of the Safe Motherhood Initiative, launched in 1987, the World Health Organization have produced and promoted a partograph with a view to improving labour management and reducing maternal and fetal morbidity and mortality. This partograph has been tested in a multicentre trial in south east Asia involving 35,484 women. Introduction of the partograph with an agreed labour-management protocol reduced both prolonged labour (from 6.4% to 3.4% of labours) and the proportion of labours requiring augmentation (from 20.7% to 9.1%). Emergency caesarean sections fell from 9.9% to 8.3%, and intrapartum stillbirths from 0.5% to 0.3%. Among singleton pregnancies with no complicating factors, the improved outcome was even more marked, with caesarean sections falling from 6.2% to 4.5%. The improvements took place among both nulliparous and multiparous women. The World Health Organisation partograph clearly differentiates normal from abnormal progress in labour and identifies those women likely to require intervention. Its use in all labour wards is recommended.

Azithromycin has antimalarial activity and favourable pharmacokinetic properties for a prophylactic antimalarial agent. We investigated the ability of azithromycin to prevent malaria in volunteers infected with a chloroquine-resistant strain of Plasmodium falciparum. 4 volunteers received oral azithromycin 500 mg followed by 250 mg daily for 7 further days. Subjects were infected on the third day of azithromycin. 3 subjects were protected compared with none of 15 controls. The volunteer not protected by azithromycin had unquantifiable plasma levels of azithromycin, probably because of poor absorption. Azithromycin could be a promising prophylactic agent for P falciparum malaria.

Recent studies have suggested that regular use of inhaled beta 2 agonists cause loss of asthma control as measured by worsening peak-flow rates, increased asthma symptoms, and more frequent need for supplementary bronchodilators. However, the magnitude of this effect and the reliability of investigator-originated definitions of control is unknown. We studied 341 people with asthma in a four-week, randomised, crossover trial of regular salbutamol (2 puffs--200 micrograms--four times daily) for two weeks and as needed for two weeks. There were no significant differences in morning and evening peak-flow rates between treatments but asthma symptoms and supplementary bronchodilator use were significantly less frequent when salbutamol was given regularly. Asthma episodes occurred 1.39 (1.52) times per day during regular treatment and 2.44 (1.75) times per day during as-needed treatment (p < 0.0001) and 0.50 (0.56) vs 0.65 (0.66) times per night (p < 0.0001). Daytime use of supplementary salbutamol was 1.14 (1.40) vs 2.35 (1.71) puffs per day, (p < 0.0001); night-time use was 0.45 (0.55) vs 0.64 (0.66) puffs per night (p < 0.0001). When control endpoints were compared between treatment periods for each individual by two blinded investigators and control judged by six different sets of criteria, in 70 asthmatics there was no difference in symptom control between periods but in the remainder, control was achieved more often by regular than by as-needed salbutamol (166 vs 69, p < 0.0001). In asthma of moderate severity, regularly administered salbutamol does not produce lower peak flow rates than as-needed salbutamol and is associated with less frequent asthma symptoms.

Randomised, double-blind controlled trials have been started to determine whether tamoxifen can prevent or delay development of breast cancer in healthy women with a family history of the disease. We recruited a randomised cohort of 111 postmenopausal women (aged 46-71 years) from the Pilot Breast Cancer Prevention Trial at the Royal Marsden Hospital to study the effect of tamoxifen on the uterus and ovaries. The main outcome measures were obtained by transvaginal ultrasonography with colour doppler imaging and microscopic examination of endometrial biopsies removed at the time of the scan. There was no significant difference between tamoxifen (20 mg/day) and placebo groups in the age of the women, or the time of the scan (and sampling) after randomisation. Women taking tamoxifen had a significantly larger uterus and a lower impedance to blood flow in the uterine arteries. 39% of women taking tamoxifen had histological evidence of an abnormal endometrium compared with 10% in the control group. 10 patients in the tamoxifen group (16%) had atypical hyperplasia and another 5 (8%) had a polyp. Women with a histological abnormality had a significantly thicker endometrium and a decreased impedance to blood flow in the uterine arteries. There was no correlation between the presence of uterine abnormalities and the age of the women, or the concentrations of tamoxifen or desmethyl tamoxifen in the peripheral blood. These findings confirm that tamoxifen can cause potentially malignant changes in the endometrium of postmenopausal women. Transvaginal ultrasonography can be used to identify those women who should have endometrial samples removed for microscopic analysis.

Growth failure is a psychosocial problem for many patients who have undergone renal transplantation. 18 adolescents (mean age 15.6, range 11.3-19.5) with severe growth retardation after renal transplantation were treated with biosynthetic growth hormone (GH) for 2 years. All received prednisone, administered daily or on alternate days, with azathioprine and/or cyclosporin A. 16 were blindly assigned to one of two GH doses (4 vs 8 IU per m2 per day). Growth, bone maturation, renal graft function, plasma insulin-like growth factors, serum binding proteins, and other biochemical parameters were checked regularly. Glomerular filtration rate and effective renal plasma flow were tested with 125I-Thalamate and 131I-Hippuran. Data on growth and glomerular filtration rate during GH treatment were also compared with those of matched non-GH-treated controls. Mean (standard deviation) increment in height after 2 years of GH was 15.7 (5.1) cm, significantly greater (p < 0.0001) than in matched controls, 5.8 (3.4) cm. Results were similar for the two GH dosage groups. Bone maturation was not accelerated. Glomerular filtration rate and effective renal plasma flow did not change significantly. The incidence of a > 25% reduction in glomerular filtration rate over 2 years was not significantly higher in GH-treated patients than in non-GH-treated controls (39% vs 32%, p = 0.97). Although a few patients had deterioration of graft function, we could not find a relation with GH treatment. Our results show that sustained improvement of height can be achieved with GH in severely growth-retarded adolescents after renal transplantation.

The overall survival in patients with gastric cancer is low, even among those undergoing resection. It has been hoped that the development of adjuvant therapy might improve survival in patients following surgery when tumour burden was minimal and both chemotherapy and radiotherapy have been proposed as suitable for use in gastric cancer. Their value has been evaluated by the British Stomach Cancer Group Second adjuvant therapy trial. 436 patients entered a prospective, randomised, controlled trial of adjuvant radiotherapy or cytotoxic chemotherapy with mitomycin, doxorubicin, and fluorouracil after gastrectomy for adenocarcinoma. After at least 5 years, there have been 372 deaths of which 7 were due to surgical complications and 327 from recurrent cancer. Following stratified randomisation, 145 patients were allocated to surgery alone, 153 to receive adjuvant radiotherapy, and 138 to adjuvant combination chemotherapy. The overall 2-year and 5-year survival were 33% (95% confidence interval 31-35%) and 17% (13-21%). No survival advantage has been shown for those patients receiving either adjuvant therapy compared to those undergoing surgery alone. The 5-year survival for surgery alone was 20%, for surgery plus radiotherapy 12%, and for surgery plus chemotherapy 19%. Surgery, therefore, remains the standard treatment for this condition and the use of adjuvant treatments should be restricted to controlled trials.

The efficacy of iron supplementation for iron-deficient subjects is in no doubt. However, the assumption that iron supplementation of iron-replete subjects is harmless may not be valid. We have studied the effect of iron supplementation on growth rate in 47 iron-sufficient young children (12-18 months) in Indonesia. The children were randomly assigned either ferrous sulphate (3 mg/kg daily) or placebo every day for 4 months. Before treatment the length, weight, and arm circumference of the two groups were similar. During the 4 months of supplementation the rate of weight gain was significantly greater in the placebo group than in the iron-supplemented group (0.106 [SE 0.010] vs 0.070 [0.011] kg every 2 weeks, p = 0.02). The rates of gain in length and arm circumference did not differ significantly by treatment. There were no differences between the groups in rates of respiratory and gastrointestinal infections. These results suggest that iron supplementation of iron-replete children may retard their growth.

Laparoscopic surgery benefits patients because it reduces pain and enables earlier mobilisation. There is concern that laparoscopic hernia repair may enter surgical practice without proper evaluation. We have done a randomised, prospective study comparing laparoscopic and open inguinal hernia repair performed under day-case general anaesthesia. 150 patients were randomised to have laparoscopic (group L) or open (group O) herniorrhaphy. Group L underwent transabdominal stapling of preperitoneal Prolene mesh. Group O underwent open repair, with a tension-free nylon darn. Postoperatively patients completed pain analogue scales eight times over 7 days, and use of analgesia was recorded. Time of return to normal domestic activity and to work was assessed. The groups were similar in age, sex, and body surface area. Self-administered co-proxamol was a median of 18 tablets (1 tablet = 325 mg) in group O (n = 75) and 6 in group L (n = 75, p < 0.001). Overall mean pain analogue score was 3.1 (SD 1.8, n = 70) in group O and 1.8 (SD 1.1, n = 71) in group L (p < 0.0001). Return to normal domestic activity was a median of 7 days in group O (n = 72) and 3 days in group L (n = 73) (p < 0.001). Return to work was a median of 28 days in group O (n = 39) and 14 days in group L (n = 40) (p < 0.002). These data suggest that laparoscopic hernia repair induces less pain than open hernia repair, and enables patients to return to normal activity and work more quickly.

Clinical trials may lead to conflicting results. We studied how different ways of reporting results affected physicians' recommendations. A questionnaire distributed to 148 general practitioners presented results of a clinical trial where a reduction of cardiac events and an increase of mortality was reported. Results were shown in four different ways--relative risk reduction, absolute risk reduction, percentages of event-free patients, number needing to be treated to prevent an event--as if they derived from different trials. A fifth presentation was the reduced rate of cardiac events along with the increased rate of mortality. Physicians were asked to estimate how much they would be willing to prescribe each drug. The mean agreement of physicians' decisions was 77 (28)% for relative risk reduction, 24 (28)% for absolute risk reduction, 37 (37)% for different percentages event-free patients, 34 (34)% for number need to treat, and 23 (28)% for events reduction and mortality for increase (p < 0.001 relative risk vs others). The method of reporting trial results and the completeness of information in the case of controversial results affects physicians willingness to prescribe.